Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA). OPA tumors consist of transformed secretory epithelial cells of the lung and have morphological resemblance to that of a human lung cancer, bronchioloalveolar carcinoma (BAC). Lung cancer is the leading cause of cancer mortality in the United States. BAC accounts for approximately 25 percent of all human lung cancers and the incidence of BAC appears to be rising. The etiology of BAC is currently unknown, which illuminates the importance of JSRV as a unique tool to investigate the molecular mechanism of lung carcinogenesis. Preliminary experiments have demonstrated that expression of JSRV Env is necessary for transformation of rodent fibroblasts and that the cytoplasmic tail plays a central role in transformation. In this proposal, we will characterize the molecular mechanism of JSRV Env-induced cell transformation. Specific aims include: 1) Identification of amino acid residues in the JSRV Env cytoplasmic tail responsible for transformation; 2) Characterization of the role of cellular proteins, including AKT and p38, in JSRV-induced transformation. These experiments will generate new insight into the molecular mechanism of oncogenesis by JSRV.